Integration of trastuzumab (T), with or without pertuzumab (P), into perioperative chemotherapy (CT) of HER-2 positive gastric (GC) and esophagogastric junction cancer (EGJC): First results of the EORTC 1203 INNOVATION study, in collaboration with the Korean Cancer Study Group, and the Dutch Upper GI Cancer group.
Authors: Anna Dorothea Wagner, Heike I. Grabsch, Murielle Mauer, Uberto Fumagalli Romario, Yoon-Koo Kang, Olivier Bouche, Sylvie Lorenzen, Markus H. Moehler, Peter C. Thuss-Patience, Anneli Elme, Gunnar Folprecht, Uwe Marc Martens, Denis Michel Smith, Maria del Carmen Galan Guzman, Michel Pierre Ducreux, Marc Díez Garcia, Guillaume Piessen, Sun Young Rha, Maike Collienne, Florian Lordick
Journal: Journal of Clinical Oncology (2023)

4057 Background: 10-20% of GC are HER-2 positive. The role of perioperative anti-HER2-directed treatment is yet undefined. Methods: This randomized, open-label phase II-trial investigates the benefit of combining T alone or with P and perioperative CT for GC and EGJC. Between 2015 and 2021,172 of a planned 215 patients (pts) with centrally confirmed, positive HER-2 status and resectable GC or EGJC (UICC TNM stages Ib-III) were included. Recruitment was prematurely terminated due to slow accrual. Pts were randomized in a 1:2:2 ratio to: Arm A (CT alone) (35 pts); Arm B (CT+ T [8mg/kg, followed by 6mg every 3 weeks]) (67 pts); Arm C (CT + T+ P [840mg every 3 weeks]) (70 pts). CT was initially cisplatin (80 mg/m 2 d1) and capecitabine (2 x 1000 mg/m 2 /d d1) for 3 cycles before and after surgery. After publication of the FLOT-4 study, the protocol was amended. CT changed to four cycles FLOT (Al-Batran Lancet 2019) with FOLFOX or CAPOX as alternative for pts ineligible for FLOT. In the experimental arms, T and P were continued beyond CT at the same dose for a total of 17 cycles. Major pathological response rate (mpRR) determined by central pathology review was the primary endpoint. The study was designed to have 80% power to detect an increase in mpRR from 25% with CT to 45% with CT+T+P or CT+T with a one-sided alpha of 10%. CT+T+P was first tested versus CT and if positive, CT+T would be tested versus CT. Results: Out of 172 pts randomized, 161 fulfilled all important eligibility criteria and started their allocated treatment (per protocol population). 62.1% of pts had EGJC and 72.0% an intestinal subtype. Main CT regimens were cisplatin+capecitabine (42.2%) and FLOT (46.6%). In Arm A:B:C, 90.9%, 92.2% and 81.3% completed neoadjuvant treatment. Major reason for treatment discontinuation was toxicity (70%). Surgery was performed in 84.8%, 98.4%, 92.2% pts in Arm A:B:C. R0 resection rates were 83.9%, 90.3% and 85.9%. At present, results of central pathology review of mpRR are available for 126 out of 150 operated pts (84.0%). Pts not operated (n=11) were considered as failures for mpRR. MpRR was 23.3%, 37.0%, 26.4% in Arm A:B:C. The increase of 3.1% (80% CI: [-9.5%, 15.7%], one-sided p=0.378) in Arm C vs. A was not statistically significant. The increase in Arm B vs. A was 13.7% (80% CI: [0.7%,26.7%], one-sided p=0.099). MpRR was 33.3%, 53.3% and 37.9% in Arm A:B:C after amending the protocol while, in contrast, it was 8.3%, 16.7% and 12.5% before. Conclusions: The primary endpoint analysis did not meet the pre-specified criteria of efficacy for the combination of CT+T+P. However, CT+T showed interesting response rates, especially with FLOT as CT backbone. Follow-up data including survival is necessary to define the clinical value of this regimen. Clinical trial information: NCT02205047 .